Measuring device and methods for use therewith

ABSTRACT

The ability to switch at will between amperometric measurements and potentiometric measurements provides great flexibility in performing analyses of unknowns. Apparatus and methods can provide such switching to collect data from an electrochemical cell. The cell may contain a reagent disposed to measure glucose in human blood.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. application No. 60/521,592filed May 30, 2004, and from U.S. application No. 60/594,285 filed Mar.25, 2005, each of which is incorporated herein by reference for allpurposes.

BACKGROUND

Electrochemical reactions may be used to measure quantities andconcentrations in solutions.

FIG. 1 is a schematic diagram of an electrochemical interface apparatus,also known as a potentiostat, for a standard three-electrodeconfiguration. Electrochemical cell 39 has a reference electrode 37, acounter electrode 36, and a working electrode 38. The cell 39 contains asubstance being analyzed as well as a reagent selected for its utility.The reagent forms part of an electrochemical reaction. It will beappreciated that there are other circuits that can accomplish thefunctions described here, and that this is only one embodiment thereof.

A voltage is applied to the cell at 36, based upon a voltage inputprovided at input 34. This voltage at 34 is defined relative to a groundpotential 40. In some embodiments this is a known voltage. Moregenerally, in a three-electrode system, the voltage at 36 assumeswhatever value is needed to make sure that the potential differencebetween 37 and 38 is substantially equal to the potential differencebetween 34 and 40.

Amplifier 35, preferably an operational amplifier, is used to providegain as needed and to provide isolation between the input 34 and theelectrodes 36 and 37. In the arrangement of FIG. 1 the gain is a unityvoltage gain and the chief function of the amplifier 35 is to provide ahigh-impedance input at 34 and to provide sufficient drive to work withwhatever impedance is encountered at electrode 36.

As the electrochemical reaction goes forward, current flows. Workingelectrode 38 carries such current. A selector 31 selects a resistor froma resistor bank 30, to select a current range for measurement of thiscurrent. Amplifier 32, preferably an operational amplifier, forms partof a circuit by which an output voltage at 33 is indicative of thecurrent through the electrode 38. The output voltage at 33 isproportional to the product of the current at 38 and the selectedresistor.

In one example, blood such as human blood is introduced into the cell. Areagent in the cell contributes to a chemical reaction involving bloodglucose. A constant and known voltage at 34 is maintained. The outputvoltage at 33 is logged and the logged data are analyzed to arrive at ameasurement of the total current that flowed during a definedmeasurement interval. (Typically this interval is such that the reactionis carried out to completion, although in some embodiments the desiredmeasurements may be made without a need for the reaction to be carriedout to completion.) In this way the glucose level in the blood may bemeasured.

As will be discussed below, the input at 34 may preferably be other thanconstant. For example it may be preferable that the input at 34 be awaveform selected to optimize certain measurements. The analog output ofa digital to analog converter may be desirably connected at input 34,for example.

The measurement just described may be termed an “amperometric”measurement, a term chosen to connote that current through the reactioncell is what is being measured.

In some measurement situations it is possible to combine the counterelectrode and the reference electrode as shown in FIG. 2, into a singleelectrode 41.

One example of a prior art circuit is that shown in German patentapplication DE 41 00 727 AI published Jul. 16, 1992 and entitled“Analytisches Verfahren fur Enzymelektrodensensoren.” That circuit,however, does not, apparently, perform an amperometric measurement uponthe reaction cell. That circuit appears to perform voltage readings, andan integrated function of voltage, with respect to a reference electrodeof a cell (relative to a working electrode of the cell) and not withrespect to a counter electrode (relative to the working electrode of thecell).

In this circuit the measured potential is a function of (among otherthings) the concentration of an analyte. Stating the same point indifferent terms, this circuit does not and cannot yield a signal that isindependent of concentration of the analyte.

SUMMARY OF THE INVENTION

FIG. 3 shows an improvement upon the previously described apparatus. InFIG. 3, an ideal voltmeter 42 is provided which can measure thepotential across the electrodes 41, 38. Switch 44 is provided which isopened when the potential is to be measured. In this way the cell 39 isfloating” as to at least one of its electrodes, permitting a voltagemeasurement that is unaffected by signals at the amplifier 35.

The switch 44 may be a mechanical switch (e.g. a relay) or an FET(field-effect transistor) switch, or a solid-state switch. In a simplecase the switch opens to an open circuit; more generally it could opento a very high resistance.

The ability to switch at will between amperometric measurements andpotentiometric measurements provides great flexibility in performinganalyses of unknowns. The various potential benefits of this approachare discussed in some detail in co-pending U.S. application Ser. No.10/924,510, filed Aug. 23, 2004 and incorporated herein by reference forall purposes. Measurement approaches are discussed in some detail inU.S. application Ser. No. 10/907,815, filed Apr. 15, 2005, and in U.S.application Ser. No. 10/907,813, filed Apr. 15, 2005, each of which isincorporated by reference.

DESCRIPTION OF THE DRAWING

The invention will be described with respect to a drawing in severalfigures.

FIG. 1 is a schematic diagram of an electrochemical interface apparatus,also known as a potentiostat, for a standard three-electrodeconfiguration.

FIG. 2 shows an arrangement in which the counter electrode and thereference electrode are combined into a single electrode 41.

FIG. 3 shows an improvement upon the previously described apparatusaccording to the invention

FIGS. 4a and 4b show embodiments in which two switches are used ratherthan the single switch of FIG. 3.

FIGS. 4c and 4d show embodiments in which one switch is used to effectthe isolation.

FIGS. 5a, 5b, and 5c show a three-electrode cell system in which it ispossible to introduce voltage measurements by providing three switches.

FIGS. 6a, 6b and 6c show a three-electrode cell system in which twoswitches are employed.

FIGS. 7a, 7b, and 7c show a three-electrode cell system in which it ispossible to introduce voltage measurements by providing one switch.

FIGS. 8a, 8b, and 8c show a three-electrode cell system in which anotherway is shown to introduce voltage measurements by providing one switch.

FIG. 9 is a test instrument 70 in side view.

FIG. 10 shows an exemplary schematic diagram of a measurement systemaccording to the invention, in greater detail than in the previousfigures.

FIG. 11 is a perspective view of a test instrument 70.

FIG. 12 shows a strip having the ability to serve as an opticalwaveguide.

FIG. 13 shows a functional block 62 which can be the analysis circuit ofany of the previously discussed figures.

FIG. 14 shows how, with proper use of analog switches, the number ofoperational amplifiers may be reduced to as few as two.

DETAILED DESCRIPTION

Variations upon the topology will now be described.

FIGS. 4a and 4b show embodiments in which two switches are used ratherthan the single switch of FIG. 3. In each embodiment, two switches areopened to isolate the cell for purposes of voltage measurement by meansof voltmeter 42.

In FIG. 4a , switches 45, 46 are opened to isolate the two-electrodecell 39 from the output of amplifier 35 and from the feedback path tothe inverting input of amplifier 35.

In FIG. 4b , switches 44, 47 are opened to isolate the two-electrodecell 39 at both the electrode 41 and the electrode 38.

FIGS. 4c and 4d show embodiments in which one switch is used to effectthe isolation. In each embodiment, a single switch is opened to isolatethe cell for purposes of voltage measurement by means of voltmeter 42.

In FIG. 4c , switch 46 is opened to isolate the two-electrode cell 39from the output of amplifier 35.

In FIG. 4d , switch 47 is opened to isolate the two-electrode cell 39 atthe electrode 38.

In FIGS. 4a, 4b, 4c, and 4d , and indeed in many examples that follow, asingle feedback resistor 43 is shown for simplicity, and is meant torepresent the selector 31 and the current-range resistors 30.

In a three-electrode cell system (see for example FIG. 1) it is possibleto introduce voltage measurements by providing three switches, as shownin FIGS. 5a, 5b, and 5c . In each embodiment, switch 46 isolates theelectrode 36 from the output of amplifier 35, switch 45 isolates theelectrode 37 from the feedback path of amplifier 35, and switch 47isolates the electrode 38 from the amperometric circuitry 32. In thisway all three electrodes of the cell 39 are “floating” relative to othercircuitry.

It is then possible to use a voltmeter to measure voltages. The voltagebeing measured is between the reference electrode 37 and the workingelectrode 38 (FIG. 5a ), or between the counter electrode 36 and theworking electrode 38 (FIG. 5b ), or between the reference electrode 37and the counter electrode 36 (FIG. 5c ).

It will be appreciated that in some analytical applications, it may bedesirable to measure more than one potential difference betweenelectrodes of the cell.

In a three-electrode cell system it is possible to introduce voltagemeasurements by providing two switches, as shown in FIGS. 6a, 6b , and 6c.

In FIGS. 6a and 6c , switch 45 isolates the electrode 37 from thefeedback path of amplifier 35.

In FIGS. 6a and 6b , switch 47 isolates the electrode 38 from theamperometric circuitry 32.

In FIGS. 6b and 6c , switch 46 isolates the electrode 36 from the outputof amplifier 35.

In this way two of the three electrodes of the cell 39 are “floating”relative to other circuitry.

It is then possible to use a voltmeter to measure voltages. The voltagebeing measured is between the reference electrode 37 and the workingelectrode 38 (FIG. 6a ), or between the counter electrode 36 and theworking electrode 38 (FIG. 6b ), or between the reference electrode 37and the counter electrode 36 (FIG. 6c ). It should be borne in mind thatsuch potential difference measurements may be made between any twopoints that are electrically equivalent to the two points of interest.Thus, for example, in FIG. 7a or 7 b, the voltmeter 42, instead of beingconnected to electrode 38, could be connected instead to ground (whichis one of the inputs of amplifier 32). This is so because the action ofthe amplifier 32 is such that the potential at 38 is forced to be at orvery near the potential at the grounded input to the amplifier. In FIGS.7c, 8a, and 8c , the voltmeter 42, instead of being connected toelectrode 37, could be connected with the electrically equivalent (sofar as potential is concerned) point 34.

In a three-electrode cell system it is possible to introduce voltagemeasurements by providing one switch, as shown in FIGS. 7a, 7b, and 7c .In each case, switch 46 isolates the electrode 36 from the output ofamplifier 35.

It is then possible to use a voltmeter to measure voltages. The voltagebeing measured is between the reference electrode 37 and the workingelectrode 38 (FIG. 7a ), or between the counter electrode 36 and theworking electrode 38 (FIG. 7b ), or between the reference electrode 37and the counter electrode 36 (FIG. 7c ).

In a three-electrode cell system there is another way to introducevoltage measurements by providing one switch, as shown in FIGS. 8a, 8b,and 8c . In each case, switch 47 isolates the electrode 38 from theamperometric circuitry of amplifier 32.

It is then possible to use a voltmeter to measure voltages. The voltagebeing measured is between the reference electrode 37 and the workingelectrode 38 (FIG. 8a ), or between the counter electrode 36 and theworking electrode 38 (FIG. 8b ), or between the reference electrode 37and the counter electrode 36 (FIG. 8c ).

It should also be appreciated that this approach can be generalized tocells with more than three electrodes.

FIG. 10 shows an exemplary schematic diagram of a measurement systemaccording to the invention, in greater detail than in the previousfigures, and corresponding most closely to the embodiment of FIG. 3.

Resistor bank 30 may be seen, which together with selector 31 permitsselecting feedback resistor values for amplifier 32. In this way theoutput at 33 is a voltage indicative of the current passing throughworking electrode 38. This corresponds to the amperometric circuitry ofFIG. 3. Selector 31 in this embodiment is a single-pole double-throwswitch with selectable sources S1, S2 and a destination D, controlled bycontrol input IN, connected to control line 53.

Two-electrode cell 39 may be seen in FIG. 10, with electrode 41 servingas combined counter electrode and reference electrode.

Integrated circuit 50 of FIG. 10 contains four switches. One of theswitches of circuit 50 is a switch 55 at pins 8, 6, 7 (input 4, source4, and drain 4 respectively). This switch 55 corresponds to switch 44 inFIG. 3, and isolates the electrode 41 from the driver of amplifier 35.When the switch 55 is opened, it is possible to use amplifier 51 as avoltmeter, measuring the voltage between inverting pin 2 andnoninverting pin 3, thereby measuring the voltage between the twoelectrodes 38, 41 of the cell 39. The voltage at output 52 isproportional to the voltage measured at the inputs of amplifier 51.

The opening and closing of the switch 55 is controlled by control line54. (It should also be appreciated that with appropriate switching, asdiscussed below, it is possible to use a smaller number of amplifiers ina way that fulfills the roles of both the amperometric circuitry and thepotentiometric circuitry.)

What is shown in FIG. 10 is thus a powerful and versatile analysiscircuit that permits at some times measuring voltage across theelectrodes of an electrochemical cell, and that permits at other timesperforming amperometric measurements across those same electrodes. Thispermits an automated means of switching between modes. In this way theapparatus differs from prior-art electrochemical analytic instrumentswhich can operate in a potentiostat (amperometric) mode or in agalvanostat (potentiometric) mode, but which require a human operator tomake a manual selection of one mode or the other.

In addition, it will be appreciated that the apparatus of FIG. 10 canalso monitor voltage during an amperometric measurement if certainswitches are closed. In other words, the amperometric and potentiometricmeasurements need not be at exclusive times.

It will also be appreciated that the switching between amperometric andpotentiometric modes need not be at fixed and predetermined times, butcan instead be performed dynamically depending upon predeterminedcriteria. For example a measurement could initially be an amperometricmeasurement, with the apparatus switching to potentiometric measurementafter detection of some particular event in the course of theamperometric measurement.

Among the powerful approaches made possible by such a circuit is to usean amperometric mode to generate a chemical potential, which can thenitself be measured by potentiometry.

Turning now to FIG. 13, what is shown is a functional block 62 which canbe the analysis circuit of any of the previously discussed figures. Avoltage input 34 may be seen as well as an output 33 indicative ofcurrent in an amperometric measurement. The functional block 62 maycomprise a three-terminal reaction cell 39 or a two-terminal reactioncell 39 as described in connection with the previously discussedfigures.

Optionally there may be a voltage output 52 indicative of voltagemeasured by a voltmeter 42, omitted for clarity in FIG. 13. In such acase, one or two or three switches (also omitted for clarity in FIG. 13)are used to isolate the cell 39 to permit potential (voltage)measurement.

Importantly in FIG. 13, input 34 is connected to a digital-to-analogconverter (DAC) 60 which receives a digital input 61. In the mostgeneral case the DAC is a fast and accurate DAC, generating complexwaveforms as a function of time at the output 63 which is in turnconnected with the input 34 of the block 62.

In some cases it may turn out that the DAC can be a less expensivecircuit. For example it may turn out that it can be a simple resistorladder connected to discrete outputs from a controller. As anotherexample it may turn out that a pulse-width-modulated output from acontroller can be used to charge or discharge a capacitor, giving riseto a desired output at 63 and thus an input at 34. Such a circuit may beseen for example in co-pending application Ser. No. 10/907,806, whichapplication is incorporated herein by reference for all purposes.

In this way it is possible to apply time-varying waveforms to reactioncells 39, for example ramps and sinusoids.

The benefits of the invention, for example the use of automaticallycontrolled switching between amperometric and potentiometric modes, andthe use of time-variant voltage inputs for the amperometricmeasurements, offer themselves not only for the glucose measurementmentioned above, but for myriad other measurements including bloodchemistry and urine chemistry measurements, as well as immunoassays,cardiac monitoring, and coagulation analysis.

Turning now to FIG. 11, what is shown is a perspective view of a testinstrument 70. A display 71 provides information to a user, andpushbuttons 78, 79, 80 permit inputs by the user. Display 71 ispreferably a liquid-crystal display but other technologies may also beemployed. Large seven-segment digits 72 permit a large portrayal of animportant number such as a bloodglucose level.

Importantly, a rectangular array of low-resolution circles or otherareas can show, in a rough way, qualitative information. This mayinclude hematocrit level, a multi-day history trend graph, a fillingrate, a temperature, a battery life, or memory/voice-message spaceremaining. The array can also be used to show progress bars” which helpthe human user to appreciate that progress is being made in a particularanalysis. The array may be fifteen circles wide and six rows high.

Thus one way to use the display is to show a very rough bar graph inwhich the horizontal axis represents the passage of time and in whichthe vertical axis represents a quantity of interest. For each timeinterval there may be none, one, two, or three, four, five, or sixcircles turned on, starting from the bottom of the array.

Another way to use the display is to show a very rough bar graph withbetween none and fifteen circles turned on, starting at the left edge ofthe array.

In this way, at minimal expense, a modest number of circles (in thiscase, ninety circles) may be used in a flexible way to show quantitativeinformation in two different ways. The circles are preferably addressedindividually by means of respective traces to a connector at an edge ofthe liquid-crystal display. Alternatively they may be addressed by rowand column electrodes.

The number of circles in a row may be fifteen.

Turning now to FIG. 9, what is shown is a test instrument 70 in sideview. A test strip 90, containing an electrochemical cell 39 (omittedfor clarity in FIG. 9), is inserted into the test instrument 70 by meansof movement to the right in FIG. 9.

It will be appreciated that the user of the test instrument 70 may havedifficulty inserting the test strip 90 into the instrument 70. This mayhappen because the user has limited hand-eye coordination or limitedfine-motor control. Alternatively, this may happen because the user isin a place that is not well lit, for example while camping and at night.In either case, the user can benefit from a light-emitting diode (LED)91 which is used to light up the area of the test strip 90. There is aconnector 93 into which the strip 90 is inserted, and the LED 91 ispreferably illuminated before the strip 90 is inserted.

In one prior art instrument there is an LED at a connector like theconnector 93, but it only can be turned on after the strip like strip 90is inserted. As such it is of no help in guiding the user in insertionof the strip.

Importantly, then, with the apparatus of FIG. 9, the user can illuminatethe LED before inserting the strip. This may be done by pressing abutton, for example. This may cast light along path 92, illuminating thetip of the strip. It may also cast light upon the connector 93, or both.

It may also be helpful to illuminate the tip of the strip in a differentway. The strip 90 as shown in FIG. 12 may have the ability (due to beingpartly or largely transparent) to serve as an optical waveguide. Forexample many adhesives usable in the manufacture of such strips aretransparent. Light can pass along the length of the strip as shown at95, emitted at the end as shown at 96. In this way it is possible toilluminate the lanced area (the area that has been pricked to produce adrop of blood) so that the tip of the strip 90 can be readily guided tothe location of the drop of blood.

The light-transmitting section of the strip 90 may be substantiallytransparent, or may be fluorescent or phosphorescent, so that the striplights up and is easy to see.

Experience with users permits selecting an LED color that is well suitedto the task. For example a blue LED will offer very good contrast whenthe user is trying to find a drop of red blood, working better than ared LED.

Turning now to FIG. 14, a circuit requiring only two operationalamplifiers 122, 137 is shown. Central to the circuit is reaction cell130 having a working electrode 120 and a counter electrode 121.Operational amplifier 122 serves as a unity-gain amplifier (buffer)applying voltage V2 to the working electrode 120. Pulse-width-modulatedcontrol line 123 turns transistors 124, 125 on and off to develop somedesired voltage through low-pass filter network 126. This developedvoltage V2 is measured at line 127, which in a typical case goes to ananalog-to-digital converter for example at a microcontroller, allomitted for clarity in FIG. 14.

The manner of operation of the pulse-width-modulated line 123 isdescribed in more detail in copending application Ser. No. 10/907,806,entitled “Method and apparatus for providing stable voltage toanalytical system”, filed Apr. 15, 2005, which application is herebyincorporated herein by reference for all purposes.

During the amperometric phase of analysis, switch 133 is open andswitches 134 and 132 are closed. A reference voltage VREF at 136develops a voltage VI (135) which is measured, preferably by means of ananalog-to-digital converter omitted for clarity in FIG. 14. This voltageis provided to an input of amplifier 137, and defines the voltagepresented to the electrode 121. The voltage developed at 128 is, duringthis phase, indicative of the current through the reaction cell 130.

During the potentiometric phase of analysis, switch 133 is closed andswitches 134 and 132 are opened. In this way the potential at theelectrode 121 is made available to the amplifier 137 and from there tothe sense line 128. The voltage developed at line 128 is indicative ofthe voltage at the electrode 121, and the voltage at electrode 120 isdefined by the voltage at 127, and in this way it is possible to measurethe potential difference between the electrodes 120, 121. Describing theapparatus differently, what is seen is an apparatus used with a reactioncell having a first electrode and a second electrode. A voltage sourceprovides a controllable voltage to the first electrode and a voltagesensor senses voltage provided to the first electrode. An amplifier iscoupled with the second electrode by way of a switch means. The switchmeans is switchable between first and second positions, the switch meansin the first position disposing the amplifier to measure current throughthe second electrode, thereby measuring current through the reactioncell. The switch means in the second position disposes the amplifier tomeasure voltage present at the second electrode. The switch means in anexemplary embodiment comprises first, second, and third analog switches,the first analog switch connecting the second electrode and an invertinginput of the amplifier, the second analog switch connecting the secondelectrode and a non-inverting input of the amplifier, the third analogswitch connecting the non-inverting input of the amplifier and areference voltage. The first position is defined by the first and thirdswitches being closed and the second switch being open, while the secondposition is defined by the first and third switches being open and thesecond switch being closed.

Returning to FIG. 14, a low-pass filter 129 is provided to smooth thesignal at line 128.

It will be appreciated that if amplifiers suitable for use in thisanalysis are expensive, and if analog switches suitable for use at 132,133, 134 are inexpensive, then it is desirable to employ a circuit suchas is shown here to permit minimizing the number of amplifiers needed.

Those skilled in the art will have no difficulty devising myriad obviousimprovements and variations upon the embodiments of the inventionwithout departing from the invention, all of which are intended to beencompassed by the claims which follow.

What is claimed is:
 1. An apparatus for use with a reaction cell havinga first electrode, a second electrode, and a third electrode theapparatus comprising: a voltage or current source providing acontrollable voltage or current to the first electrode; a voltmeter; anamplifier; an amperometric circuitry; and switching means, said switchmeans being configured to float two of the first, second and thirdelectrodes with respect to circuitry outside of the reaction cell,wherein the switching means is configured to isolate the first electrodefrom a feedback path of the amplifier, the second electrode from theamperometric circuitry, and the third electrode from the output of theamplifier.
 2. A system for switching between amperometric andpotentiometric measurements, the system comprising: a reaction cellcomprising first, second, and third electrodes; a voltage or currentsource providing a controllable voltage or current to the firstelectrode; a voltmeter; an amplifier; an amperometric circuitry; andswitching means, said switch means being configured to float two of thefirst, second and third electrodes with respect to circuitry outside ofthe reaction cell, wherein the switching means is configured to isolatethe first electrode from a feedback path of the amplifier, the secondelectrode from the amperometric circuitry, and the third electrode fromthe output of the amplifier.